Infection & Chemotherapy

한국인에서 발생된 HLA-B*57:01 관련 Abacavir Hypersensitivity

의 첫 증례윤지현・김민구・진성준・김승규・이서희・천재영・윤지영・김민경・하지윤・송영구

연세대학교 의과대학 내과학교실

Case Report

Submitted: April 10, 2012Revised: May 18, 2012Accepted: May 18, 2012Correspondence to Young Goo Song, MD., PhD.Division of Infectious Disease, Departement of Internal Medicine, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul 135-720, KoreaTel: +82-2-2019-3319, Fax: +82-2-3464-3882E-mail: imfell@yuhs.ac

http://dx.doi.org/10.3947/ic.2012.44.5.399

Infect Chemother 2012;44(5):399-402

pISSN 2093-2340 eISSN 2092-6448

www.icjournal.org

The First Case of Abacavir Hypersensitivity Associated with the HLA-B*57:01-Positive Allele in Korea

On the 12th day of abacavir treatment, a 39-year old HIV-infected male patient was

admitted with fever, generalized rash, abdominal pain, and watery diarrhea that

had persisted for five days. Results of blood tests indicated rapid progression of

hepatitis and renal failure. The day after stopping anti-retroviral therapy, his fever

subsided and his liver function began to normalize. He was clinically diagnosed with

abacavir hypersensitivity and was found to carry the HLA-B*57:01 allele. This is the

first reported case of abacavir hypersensitivity associated with the presence of the

HLA-B*57:01 allele in Korea.

Key Words: Abacavir, Hpersensitivity, HLA-B*57:01, Korea

Ji Hyun Yoon, Mingoo Kim, Sung Joon Jin, Seung Kyu

Kim, Seo Hui Lee, Jaeyoung Cheon, Gi young Yun, Min

Kyung Kim, Jiyoon Ha, and Young Goo Song

Department of Internal Medicine, Yonsei University Col-

lege of Medicine, Seoul, Korea

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Copyright © 2012 by The Korean Society of Infectious Diseases | Korean Society for Chemotherapy

Introduction

Abacavir is a nucleoside reverse-transcriptase inhibitor with activity against

the human immunodeficiency virus (HIV). A hypersensitivity reaction, which

occurs in approximately 5% of patients, is the major treatment-limiting

toxicity of abacavir [1]. Abacavir hypersensitivity reaction is characterized by

multisystem involvement, and, in rare cases, it can be fatal [2]. Median time to

onset of symptoms of hypersensitivity is 11 days. Symptoms usually appear

within at least the first six weeks [1, 2]. Common manifestations include fever,

rash, constitutional symptoms, and gastrointestinal tract symptoms. Ninety six

percent of patients have fever, rash, or both [1]. Less common manifestations

include respiratory or musculoskeletal symptoms, headache, paresthesia,

edema, renal failure, hepatic failure, and anaphylaxis. In particular, respiratory

symptoms are more severe with continued dosing [1, 3]. Symptoms related

to hypersensitivity show worsening with continued therapy and usually

show improvement within 24 hours of discontinuation [1-3]. Subsequent

use of abacavir typically results in a more severe, rapid, and potentially life

threatening reaction; therefore, re-challenge is contraindicated [1-3].

Abacavir hypersensitivity is a major adverse effect and has been identified

400 JH Yoon, et al. • Abacavir hypersensitivity www.icjournal.org

as a pharmacogenomic risk factor in association with usage

of abacavir. However, no case of abacavir hypersensitivity

associated with presence of the HLA-B*57:01 allele has been

previously reported in Korea. We report on our experience with

an HIV-infected patient carrying the HLA-B*57:01 allele who was

diagnosed with abacavir hypersensitivity.

Case Report

A 39-year-old male patient was admitted with fever, gene-

ralized rash, abdominal pain, and watery diarrhea for five days.

He had recently been diagnosed with HIV infection. Because

he had a low CD4+ cell count, 206 cells/mm3, anti-retroviral

therapy with abacavir/lamivudine and lopinavir/ritonavir was

initiated. He took abacavir/lamivudine once daily and lopinavir/

ritonavir twice daily and did not take any other medications.

Three hours after taking the first dose of abacavir/lamivudine,

he experienced myalgia. After seven days, his body temperature

rose to near 40℃ and he experienced abdominal pain and watery

diarrhea. The symptoms showed progressive worsening and the

time interval of administration of antipyretics shortened.

On admission, his blood pressure was 104/62 mmHg, heart

rate was 126 beats/min, respiratory rate was 20 breaths/min,

and body temperature was 39.1℃. No significant symptoms,

other than a generalized skin rash and mild abdominal tender-

ness, were observed on physical examinations. White blood cell

(WBC) count was 7,290/mm3, hemoglobin level was 15.1 g/dL,

and platelet count was 85,000/mm3. Levels of aspartate amino-

transferase (AST) and alanine aminotransferase (ALT) were

elevated to 940 IU/L and 478 IU/L. Total bilirubin level was 1.8

mg/dL. Blood urea nitrogen level was 16.7 mg/dL and serum

creatinine level was 1.45 mg/dL. HIV viral load was 180,000

copies/mL and CD4+ T-lymphocyte count was 305 cells/mm3.

Antibodies to hepatitis C, hepatitis A, and hepatitis B surface

antigens were absent. Findings on computed tomography (CT)

scan of the chest indicated normal lung parenchyme and small

axillar lymph nodes, and findings on a CT scan of the abdomen

indicated hepatic congestion, gallbladder wall edema, and mild

splenomegaly (Fig. 1). Results of blood and stool cultures were

negative. Liver function showed rapid worsening; therefore, all

medications were discontinued. The day after stopping anti-

retroviral agents, the patient’s fever subsided and AST and ALT

levels began to decrease (Table 1). Human leukocyte antigen

(HLA)-B typing was performed. He was found to have the

HLA-B*37:01 and B*57:01 alleles. He was believed to be suffering

from abacavir hypersensitivity. Three weeks after stopping

abacavir, he exhibited no symptoms and all laboratory findings

Figure 1. (A, B) Computer tomographic images of the abdomen show hepatic congestion, mild splenomegaly, and gallbladder edema. (C, D) Computer tomograpic images of the chest show normal lung parenchyme and small axillar lymph nodes.

A B

C D

http://dx.doi.org/10.3947/ic.2012.44.5.399 • Infect Chemother 2012;44(5):399-402 401www.icjournal.org

were normalized. This is the first reported case of a patient with

abacavir hypersensitivity associated with the HLA-B*57:01 allele

in Korea.

Discussion

This is the first reported case involving abacavir hypersen-

sitivity in a Korean patient who was found to harbor the HLA-

B*57:01 allele. On the seventh day after initiation of abacavir

treatment, he developed a fever, abdominal pain, and watery

diarrhea. Hepatitis and renal failure showed rapid progression.

The day after cessation of abacavir intake, the patient's symptoms

began to diminish. Within the next three months, he had made a

full recovery from his hypersensitivity reaction and his laboratory

findings were normal.

There are several clinical criteria for diagnosis of abacavir

hypersensitivity. First, symptoms must occur within six weeks

of the start of abacavir treatment. Second, more than two of

the following symptoms must be observed: fever, rash, and

gastrointestinal, constitutional, or respiratory symptoms. Third,

symptoms should be alleviated within three days after cessation

of abacavir treatment. Finally, the symptoms cannot be explained

by other causes [1-3]. As observed in the present case, the patient

fulfilled all of these criteria, including both the timing of the onset

of symptoms and the actual symptoms observed.

Skin patch testing has been used successfully as an adjunct

to clinical diagnosis to aid in identification of patients with

immunologically-mediated abacavir hypersensitivity. One

patch panel uses 1% and 10% concentrations of abacavir and

excipient and petrolatum controls. It is applied to the mid-back

and is removed 48 hours after placement. Results of the test are

read within 24 hours after patch removal. A positive cutaneous

reaction (erythema; induration; pruritus; and, in some cases,

vesiculation and blistering) implies immunological confirmation

of abacavir hypersensitivity [4, 5].

Both clinical diagnosis and skin patch testing have limitations.

In clinical diagnosis, a rash may also be associated with use of

efavirenz, and fever, rash, and hepatitis may also be associated

with use of nevirapine, and gastrointestinal symptoms may be

associated with use of protease inhibitors [3]. In the PREDICT-1

study, due to incidence of clinically diagnosed patients with the

HLA-B*57:01 allele who demonstrated false-negative results on

the epicutaneous patch test, a negative skin patch result could

neither rule out abacavir hypersensitivity nor justify re-challenge

[3].

In 2002, an association between diagnosis of hypersensitivity

and presence of the major histocompatibility complex class I

allele HLA-B*57:01 was reported independently by two research

groups [2, 6]. In the PREDICT-1 study, HLA-B*57:01 screening

was proven to reduce the risk of hypersensitivity reactions

to abacavir [3]. Currently, all patients are recommended to

undergo screening for the HLA-B*57:01 allele before receiving a

prescription for abacavir.

Carriage frequencies of the HLA-B*57:01 allele in the United

States are 5% among African-Americans and 8% among

Caucasians: the prevalence of abacavir hypersensitivity is

4% among HIV-positive African-Americans and 5% among

Caucasians [7, 8]. Previous studies have reported on a low

prevalence of the HLA-B*57:01 allele in East-Asians; only one

(0.3%) of 320 HIV-infected Taiwanese patients carries the allele

[9]. Frequency of the HLA-B*57:01 gene in healthy Koreans

is reported to be 0.2-0.3% [10] and has not been reported to

occur among HIV-infected Koreans thus far. In 2009, Park et al,

who investigated HLA-B*57:01 and abacavir hypersensitivity in

Korean HIV-infected patients [11], found neither HLA-B*57:01

carrier nor immunologically confirmed abacavir hypersensitivity.

They suggested that because of a low prevalence of the allele,

HLA-B*57:01 screening in Asians might not be as useful.

Therefore, despite the guidelines, most Korean patients have not

undergone screening for the presence of the HLA-B*:57:01 allele

prior to undergoing treatment with abacavir [12].

We agree that, due to the low frequency of HLA-B*57:01 and

the cost of HLA typing, screening of all Korean patients before

abacavir treatment is not necessary. However, all clinicians

prescribing abacavir should have knowledge of the severe

consequences of abacavir hypersensitivity and should also

be aware that some patients carry the allele associated with

abacavir hypersensitivity, even if at a very low frequency. In-

stead of screening, clinicians should be aware of the clinical

Table 1. Changes of Laboratory findings began to Normalize of PatientsHD1

(ART 12th Day)HD2

(ART stop)HD3 HD5 HD7

WBC (/mm3) 7,290 6,170 4,160 13,420 11,250

Hb (g/dL) 15.1 13.5 12.8 11 11

Plt (103/uL) 85 71 71 88 172

AST (IU/L) 940 995 1,175 1,971 1,293 352 110

ALT (IU/L) 478 462 595 791 636 300 235

T.Bil (mg/dL) 1.8 1.9 2.5 2.7 3.2 2 1.2

BUN (mg/dL) 16.7 22.5 18.2 6.2 6.5

Cr (mg/dL) 1.4 1.7 1.4 0.6 0.5

CRP (mg/L) 152.3 12

Procalcitonin (μg/L) 17.78 0.36

402 JH Yoon, et al. • Abacavir hypersensitivity www.icjournal.org

manifestations of abacavir hypersensitivity, and, once it is

suspected, HLA-B typing should be performed immediately.

The present case emphasizes the necessity of vigilance in

monitoring Korean patients undergoing treatment with abacavir,

as some patients may carry the allele, which is associated with

abacavir hypersensitivity, even if at a very low prevalence.

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